Because different mouse strains exhibit unique amounts of noise-induced hearing loss (NIHL), the susceptibility of cochlear function to the adverse effects of excessive sounds seems dependent on genetic background. Additionally, preliminary molecular studies in our laboratory profiled normal cochlear gene expression in two inbred strains using mouse cDNA expression arrays and showed that the cochlear levels of many expressed genes can be evaluated. In combination, the above findings indicate that the mouse is a reliable model to study the biological mechanisms of susceptibility to NIHL. Work by others linked permanent impairment of cochlear function to the production of reactive oxygen species and cellular oxidative damage after noise. Inducible mechanisms that can protect the cells from oxidative damage are also the topic of many current investigations. The proposed work will identify changes in gene expression induced by noise in susceptible and resistant mouse strains. For each inbred strain studied, the level of expression of many genes will be examined in a group of non-exposed mice as compared to a second group exposed to a standardized noise. The hypothesis to be tested is that noise susceptibility reflects the inability of specific cell types in the sensitive cochlea to induce protective mechanism(s), such as the upregulation of genes required to allow the restoration of normal function. The noise-exposure protocols proposed here have been carefully designed, based on preliminary functional data that illustrate the differential susceptibilities of the inbred strains selected for this work. The specific aims that will test this hypothesis are: (1) To identify genes that are expressed at significantly different levels after noise exposure in the cochlea of resistant and susceptible mouse strains. Hybridization experiments of mouse cDNA arrays and follow-up RNase protection and RT-PCR-based assays will be used to identify and confirm the changes in gene expression after a standardized noise in resistant and susceptible mouse strains. Cochlear RNA from groups of control (non-exposed) mice will be compared to groups of exposed mice of the same inbred strain; (2) To identify the cell types in the mouse cochlea that express each one of the transcripts found to be regulated by excessive noise. This aim will be accomplished using in situ hybridization techniques. The knowledge to be gained is essential for the long-term objective of the proposed work, i.e., to elucidate the molecular basis of susceptibility to NIHL.